The overall objective of this project is to quantify as completely as possible the detailed dynamics of thyroid hormone metabolism and distribution in the vascular and major interstitial and tissue pools of the sheep. The processes of interconversion in peripheral tissues of thyroxine (T4) to triiodothyronine (T3), and T4 to reverse T3 (RT3), are of particular interest. We propose to identify and quantify the major organ pools of extravascular T3, T4 and RT3, quantify the relative distribution and kinetics of T3, T4 and RT3 among vascular and major interstitial and tissue pools, quantify the rates of T4 to T3 conversion and T4 to RT3 conversion in various tissues or subclasses of tissues, and quantify T3, T4 and RT3 disposal in excreta. In vivo studies in the intact sheep include constant infusion or pulse dose administration of labeled iodothyronines intravenously, followed by measurement of labeled and/or stable T3, T4 and RT3, or binding protein concentrations, in plasma, specific lymphatics, specific whole tissue samples, and feces and urine. Similar studies will be performed with specific radioimmunoassay systems; and all kinetic data will be processed with the aid of explicit biosystem models and computational algorithms. Applicable results will be extrapolated to the human thyroid system.